CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification
Afam A. Okoye, Derick D. Duell, Yoshinori Fukazawa, Benjamin Varco-Merth, Alejandra Marenco, Hannah Behrens, Morgan Chaunzwa, Andrea N. Selseth, Roxanne M. Gilbride, Jason Shao, Paul T. Edlefsen, Romas Geleziunas, Mykola Pinkevych, Miles P. Davenport, Kathleen Busman-Sahay, Michael Nekorchuk, Haesun Park, Jeremy Smedley, Michael K. Axthelm, Jacob D. Estes, Scott G. Hansen, Brandon F. Keele, Jeffery D. Lifson, Louis J. Picker
Afam A. Okoye, Derick D. Duell, Yoshinori Fukazawa, Benjamin Varco-Merth, Alejandra Marenco, Hannah Behrens, Morgan Chaunzwa, Andrea N. Selseth, Roxanne M. Gilbride, Jason Shao, Paul T. Edlefsen, Romas Geleziunas, Mykola Pinkevych, Miles P. Davenport, Kathleen Busman-Sahay, Michael Nekorchuk, Haesun Park, Jeremy Smedley, Michael K. Axthelm, Jacob D. Estes, Scott G. Hansen, Brandon F. Keele, Jeffery D. Lifson, Louis J. Picker
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Research Article AIDS/HIV

CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

Abstract

To define the contribution of CD8+ T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term CD8+ T cell depletion using a rhesusized anti-CD8β monoclonal antibody on barcoded SIVmac239 dynamics on stable ART and after ART cessation in rhesus macaques (RMs). Among the RMs with full CD8+ T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV RNA+ cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and DNA in blood and tissue relative to control-treated RMs during ART. Upon ART cessation, both CD8+ T cell–depleted and control RMs rebounded in fewer than 12 days, with no difference in the time to viral rebound or in either the number or growth rate of rebounding SIVmac239M barcode clonotypes. However, effectively CD8+ T cell–depleted RMs showed a stable, approximately 2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent antiviral CD8+ T cell responses can develop during ART-suppressed SIV infection, these responses effectively intercept post-ART SIV rebound only after systemic viral replication, too late to limit reactivation frequency or the early spread of reactivating SIV reservoirs.

Authors

Afam A. Okoye, Derick D. Duell, Yoshinori Fukazawa, Benjamin Varco-Merth, Alejandra Marenco, Hannah Behrens, Morgan Chaunzwa, Andrea N. Selseth, Roxanne M. Gilbride, Jason Shao, Paul T. Edlefsen, Romas Geleziunas, Mykola Pinkevych, Miles P. Davenport, Kathleen Busman-Sahay, Michael Nekorchuk, Haesun Park, Jeremy Smedley, Michael K. Axthelm, Jacob D. Estes, Scott G. Hansen, Brandon F. Keele, Jeffery D. Lifson, Louis J. Picker

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Figure 6

Differential depletion of CD8+ T cells in tissues after anti-CD8β.

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Differential depletion of CD8+ T cells in tissues after anti-CD8β. (A an...
(A and B) Comparison of the fraction of memory (Tm) and naive CD8+ T cells of total T cells in lymph nodes (LNs) and bone marrow (BM) after 9 weeks of treatment with anti-CD8β or IgG control mAb. RMs with full CD8+ Tm depletion are shown in red (n = 7; see main text), RMs with incomplete CD8+ Tm depletion are shown in green (n = 3) with individual RMs delineated by different symbols, and IgG isotype controls are shown in blue (n = 10). Each data point represents an individual RM. Plots show jittered points with a box from first to third quartiles (IQR) and a line as the median, with whiskers extending to the farthest data point within 1.5 × IQR above and below the box, respectively. Wilcoxon’s rank-sum test was used to determine the significance of differences between treatment groups (unadjusted P values shown). (C) Immunofluorescence microscopy of representative LN sections from an RM with maximal (“complete”) CD8 depletion (middle panel), an RM with incomplete CD8 depletion (right panel), and an IgG control RM (left panel). CD8+ cells are in red, while CD20+ cells are in blue. The white line is used to demarcate the T cell zone (TCZ) and the B cell zone (BCZ). Scale bars: 100 μm. (D–F) Quantification of the number of CD8+ cells per 1 × 105 cells in LNs in TCZ, BCZ, and medullary cords (MC) of LNs at 16 days after ART release in the treatment groups. Each data point represents the average number of CD8+ cells derived from quantitative measures from 2–3 LN sections from a single time point from an individual RM. Wilcoxon’s rank-sum test was used to determine the significance of differences between treatment groups, first excluding RMs with incomplete CD8+ Tm depletion, and then including all treated RMs versus IgG controls (unadjusted P values shown). In A, B, and D–F closed symbols indicate Mamu-A*01+ RMs and open symbols indicate Mamu-B*08+ RMs.